A recent study published in the journal Nature communications The observed range of antibodies and effectors act as important immunological correlates that can be used to develop universal influenza vaccines. This vaccine could be effective against all strains of the flu virus, even those with pandemic potential.
Study: Influenza antibody range and effector functions are immunological correlates of acquisition of pandemic infection in children. Image credit: Africa Studio / Shutterstock
Record
Children are particularly vulnerable to influenza viruses that cause seasonal epidemics and sporadic pandemics. Seasonal influenza epidemics not only lead to increased hospital admissions, but also increase mortality rates in older adults with comorbidities. Many studies have shown that seasonal flu vaccines provide limited protection against influenza viruses that have the potential to cause a pandemic. However, the 2009 H1N1 (pH1N1) pandemic revealed the effectiveness of seasonal vaccines in protecting children and the elderly from infection. This protection may be due to antibody cross-reactions.
Compared to children, adults possess additional immunological correlates such as T-cell responses and non-neutralizing antibody functions. This is why children need higher concentrations of HAI antibodies for an equivalent amount of immune protection against infection. To design a next-generation vaccine, it is important to identify immunological correlates of protection. In the context of pH1N1 infection, HA strain-specific antibodies play a critical role in providing protection, which is mediated by Fc receptor (FcR) function.
Certain antibodies that can cross-react between pandemic, seasonal and bird flu viruses could reduce the severity of influenza virus infection. In this context, serum antibodies, particularly IgG, can facilitate effector functions such as directing immune cells to kill infected cells, engulfing infected cells through antibody-dependent phagocytosis (ADCP), and promoting the antibody cell cytotoxicity (ADCC). These functions are mediated by Fc gamma receptors (FcγR) 3a and FcγR2a.
Mechanistically, FcγR 3a and FcγR2a use macrophages and natural killer (NK) cells to remove virus-infected cells. Cross-reactivity of ADCC antibodies has been associated with targeting conserved antigenic sites of influenza virus hemagglutinin (HA), nucleoprotein (NP), and matrix 1 (M1).
About the Study
The current study identified several gaps in research on antibody effector functions. For example, few studies have evaluated vaccine-induced ADCC changes, longitudinal persistence of vaccine-induced FcR antibody binding and isotype shifts, and changes in HA-specific antibody responses with vaccination and infection. The current randomized placebo-controlled trial (RCT) investigated the range and function of influenza-specific antibodies of seasonal (S1) H1N1 vaccination and pH1N1 infection.
Antibody characteristics, particularly HAI titer, from seasonal vaccination that could help reduce or delay contraction of pH1N1 were assessed using selected archived samples. These samples were collected from NCT00792051, a randomized placebo-controlled trial and follow-up study that used school children between 6 and 17 years of age.
A subset of children who received any influenza vaccination in Year 1 (V1) or not (placebo-V0) were selected for secondary analyses, which helped determine the efficacy of vaccination against pH1N1 infection.
Study Findings
The current study showed that non-neutralizing antibodies are highly cross-reactive between different strains and subtypes of influenza, which could play an important role in reducing the incidence and severity of infection.
Detection of antibody functions other than HAI is crucial for the development of next-generation vaccines. This study identified serological correlates that play an important role in protecting children from pandemic infection. In 2009, when schools were closed for two months, transmission of H1N1 was low. However, shortly after schools opened in September 2009, more than 50% of students became infected within a few months. A very low community uptake of the pH1N1 monovalent vaccine has been documented.
The half-life of different antibody subclasses varies considerably. The current study observed that seasonal vaccination enhances the Fc effector functions of pH1N1-specific antibodies NP, HA, and neuraminidase (NA). However, their function was short-lived as it disappeared within a year of vaccination. A greater decrease in antibodies was observed in unvaccinated children.
Seasonal vaccination did not enhance FcR effector functions in other seasonal specific antibody responses. Unvaccinated, uninfected children also showed increased FcR-mediated effector functions of the pandemic-specific NA, HA, and NP antibodies. These children showed a higher level of antibodies to NK cell function. pH1 antibodies to H3-HA responses were associated with avian H5-specific IgG, FcγR2a, and FcγR3a cross-reactivity. This finding suggests that cross-reactions are less focused and not trained by seasonal exposure to viruses of other groups.
Considering the experimental results, vaccination and previous infection are not associated with the lack of infection in unvaccinated, uninfected children or with the susceptibility of V1S1 children. More research is needed to understand the host factors that lead to these results.
The results also showed that IgG3 antibodies specific for group 2 H3 HA are negative predictors of infection. However, pre-infection seasonal H1 and pH1-IgG3 antibodies were positively correlated and therefore protective against infection.
conclusions
This study shows how universal influenza vaccines, effective against seasonal to pandemic viruses, can be developed. Antibody breadth and FcR effector functions are two important immunological correlates that could be exploited for the development of this vaccine.
